Platelet Aggregation and Adenosine Diphosphate/Adenosine Triphosphate Receptors: A Historical Perspective

The work of many investigators since adenosine diphosphate (ADP) was recognized as a platelet aggregating agent in 1961 has led to an appreciation of the important part that ADP plays in hemostasis and thrombosis. Recently, interest has focused on the platelet receptors for ADP and adenosine triphosphate (ATP). Platelets are unique because they have two P2Y receptors that must act in concert to achieve a normal aggregation response. The P2Y(1) receptor is responsible for mobilizing internal calcium, platelet shape change, and weak aggregation. The P2Y(12) receptor inhibits adenylyl cyclase, but the concentration of cyclic AMP is reduced only if it has been raised from its low basal levels by stimulation of adenylyl cyclase by an aggregation inhibitor such as adenosine or prostaglandin I-2. The abnormal bleeding of the rare patients whose platelets lack P2Y(12) and the beneficial clinical effects of ticlopidine and clopidogrel that block this receptor indicate that P2Y(12), in addition to inhibiting adenylyl cyclase, may have an as yet unidentified role that is needed for its cooperative aggregation effect with P2Y(1). ATP 1 stimulates a rapid influx of calcium into platelets through the P2X(1) receptor, and it may synergize with ADP when these two nucleotides are released from platelets at a site of vessel injury.